There is an increased metabolic demand in sickle cell disease, resulting in a significant deficiency of L-Arginine. Recent studies have shown that adult SCD patients in vaso-occlusive crisis have low serum nitrate/nitrate levels which are the stable end product of nitric oxide (NO). Improvements in pain scales for patients inVOC parallel increases in NO production. Endothelium-derived relaxing factor has been found to be NO. L-Arg is the precursor to NO production. The L-Arg-NO pathway may prove to be very important to the pathology of SCD and offers an exciting new realm of sickle cell research. Arginine is easily available and has low toxicity. It may prove to be very beneficial in treating sickle cell disease patients, both acutely and long-term.